Figures

Abstract

Background

In Mozambique during 2004–2007 numbers of adult patients (≥15 years
old) enrolled on antiretroviral therapy (ART) increased about 16-fold, from
<5,000 to 79,500. All ART patients were eligible for co-trimoxazole. ART
program outcomes, and determinants of outcomes, have not yet been
reported.

Methodology/Principal Findings

In a retrospective cohort study, we investigated rates of mortality,
attrition (death, loss to follow-up, or treatment cessation), immunologic
treatment failure, and regimen-switch, as well as determinants of selected
outcomes, among a nationally representative sample of 2,596 adults
initiating ART during 2004–2007. At ART initiation, median age of
patients was 34 and 62% were female. Malnutrition and advanced
disease were common; 18% of patients weighed <45 kilograms, and
15% were WHO stage IV. Median baseline CD4+ T-cell
count was 153/µL and was lower for males than females (139/µL
vs. 159/µL, p<0.01). Stavudine, lamivudine, and nevirapine or
efavirenz were prescribed to 88% of patients; only 31% were
prescribed co-trimoxazole. Mortality and attrition rates were 3.4 deaths and
19.8 attritions per 100 patient-years overall, and 12.9 deaths and 57.2
attritions per 100 patient-years in the first 90 days. Predictors of
attrition included male sex [adjusted hazard ratio (AHR) 1.5;
95% confidence interval (CI), 1.3–1.8], weight <45 kg
(AHR 2.1; 95% CI, 1.6–2.9, reference group >60 kg), WHO
stage IV (AHR 1.7; 95% CI, 1.3–2.4, reference group WHO stage
I/II), lack of co-trimoxazole prescription (AHR 1.4; 95% CI,
1.0–1.8), and later calendar year of ART initiation (AHR 1.5;
95% CI, 1.2–1.8). Rates of immunologic treatment failure and
regimen-switch were 14.0 and 0.6 events per 100-patient years,
respectively.

Conclusions

ART initiation at earlier disease stages and scale-up of co-trimoxazole among
ART patients could improve outcomes. Research to determine reasons for low
regimen-switch rates and increasing rates of attrition during program
expansion is needed.

This is an open-access article, free of all copyright, and may be
freely reproduced, distributed, transmitted, modified, built upon, or otherwise used
by anyone for any lawful purpose. The work is made available under the Creative
Commons CC0 public domain dedication.

Funding: All parts of this study were funded by the United States President's
Emergency Plan for AIDS Relief (PEPFAR, http://www.pepfar.gov/)
through the U.S. Centers for Disease Control and Prevention (CDC). Authors
employed by the CDC (Drs Auld, Shiraishi, Sanchez, Alfredo, Nelson, and
Ellerbrock) contributed substantially to all parts of the study and writing of
the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Globally, during 2004–2009, the number of HIV-infected patients enrolled on
antiretroviral therapy (ART) increased more than 10-fold, from less than 400,000 to
more than five million, with most new ART patients enrolled in sub-Saharan Africa
[1]. Reporting
treatment outcomes of patients enrolled in ART programs is important to demonstrate
program effectiveness and justify continued funding, while assessment of factors
associated with outcomes can help to identify opportunities for program improvement
[2], [3]. Although many
sub-national ART programs in sub-Saharan Africa have reported their treatment
experience [4]–[12], only a few studies
can be considered nationally representative due to the large cohort size [6], [12], or
sampling design [13].

In Mozambique, where about 1.6 million people are HIV-infected and about 473,000 need
ART [14],
numbers of adult patients (≥15 years old) enrolled on ART increased about 16-fold
from less than 5,000 to 79,500 during 2004–2007 [15]. We conducted a retrospective,
cohort study among a nationally representative sample of adult ART patients starting
ART during 2004–2007, to describe mortality rates, attrition rates (numbers of
patients who died, were lost to follow-up [LTFU], or stopped ART per 100
person-years), immunologic treatment failure rates, and determinants of attrition
and treatment failure. Secondary treatment outcomes of interest were
CD4+ T-cell (CD4) count response and weight gain. Regimen-switch
rates were measured to allow comparison with rates reported from other programs.

Methods

Ethics Approval

This study was approved by the Institutional Review Board (IRB) of the United
States Centers for Disease Control and Prevention (CDC) and the Mozambican
Ethics Review Committee (Ministerio da Saude Comite Nacional de Bioetica
para a Saude). Both review boards approved the consent procedures.
Patient informed consent was not required as only routine, anonymous,
operational monitoring data were collected and analyzed.

Eligibility for ART during 2004–2007

During 2004–2007, patients diagnosed with World Health Organization (WHO)
stage IV disease, stage III disease with CD4 counts <350/µL, or stage I
or II disease with CD4 counts <200/µL, were eligible for ART [16].
Prescription of trimethoprim-sulfamethoxazole combination, or co-trimoxazole
(CTX), was indicated for all ART patients. First-line ART regimens included two
nucleoside reverse-transcriptase inhibitors (NRTI) and a non-nucleoside reverse
transcriptase inhibitor (NNRTI). Second-line regimens contained a protease
inhibitor and two new NRTIs. Before initiating ART, HIV counseling and testing
(HIV-CT) of patient partners was recommended to facilitate HIV care for infected
partners or prevention interventions for sero-discordant couples.

Patient Monitoring

At ART initiation, standardized medical records, recommended by the Ministry of
Health (MOH), were completed. These records captured, among other variables:
date of visit, sex, age at enrollment, date of birth, marital status, employment
status, HIV status of partner, WHO stage, CD4 count, weight, height, hemoglobin
level, ART regimen and CTX prescription status. At all subsequent visits, the
date of the visit, patient weight, clinical stage and ART regimen prescribed
were recorded, while at 6-monthly intervals after ART initiation, hemoglobin
measurements, and CD4 counts were recommended to monitor disease progression or
improvement. Patients collected medications monthly from clinic pharmacies where
the date of scheduled antiretroviral (ARV) pick-up appointments and actual ARV
pick-up occurrences were documented.

As in other resource-constrained settings where viral load monitoring is not
routine [6],
[13],
[17],
during 2004–2008, treatment failure was detected using clinical and
immunologic criteria. A new or recurrent stage III or IV condition was
considered clinical evidence of possible treatment failure; however,
confirmation of failure, with a CD4 measurement, was required before switching
regimens. All facilities providing ART had access to CD4 assays. Immunologic
failure criteria included a CD4 count decline from baseline, a CD4 count
<100/µL, or a 50% decline from peak CD4 count, after ≥6
months of therapy [16]. At the limited number of sites with access to viral
load testing facilities, viral load measurements were also encouraged.

Treatment Outcome Measures

Our reported mortality rate represents the number of documented deaths during ART
per 100 person-years of observed therapy. The attrition rate represents the
number of patients lost through attrition (death, LTFU, or stopping ART) per 100
person-years of observed therapy. A patient absent from a health facility in the
90 days preceding data abstraction was considered LTFU, unless the medical
record stated that the patient had died, stopped ART, or transferred. The date
of LTFU was recorded as the date of the most recent visit, or one day after ART
initiation if patients only attended the initiation visit. One-year attrition
proportions are reported to allow comparison with published literature [11], [18]. Patients
transferring to other facilities during the first treatment year were excluded
from the one-year attrition proportion. Transfers were censored from
time-to-event analyses at the date of transfer.

To allow comparison with other resource-constrained programs [6], [17], we report
incidence of the first CD4 count meeting immunologic treatment failure criteria.
Incidence of clinical failure is not reported because MOH guidelines required
that the often inaccurate diagnosis of clinical failure [19] be confirmed with
objective CD4 count measurements before a regimen change was considered. To
allow comparison with other programs in resource-limited settings, we also
report rates of regimen-switch per 100 patient-years [20].

Similar to other cohort studies in resource-constrained settings [6], adherence
to ART was estimated by measuring timeliness of patient visits to scheduled
medicine pick-up appointments at clinic-based pharmacies [21]–[23] during
the first six months of ART.

Study Design and Population

A retrospective cohort study design was used. Patient-level data were abstracted
from standardized, MOH-recommended medical records onto study questionnaires by
trained abstractors in November 2008. Only medical records of adult patients,
≥15 years old at ART initiation, who started ART during 2004–2007, were
eligible.

Sample Size

Sample size calculations were performed using Epi Info™ software (CDC, Epi
Info 2008, Version 3.5.1, Atlanta, GA). To achieve a 95% confidence
interval (CI) of ±3.0% around the estimate for 6-month attrition,
assuming a design effect of 1.5, and a conservative (i.e. higher than expected)
6-month attrition proportion of 25% [11], a sample size of ≥1,200
patient records was needed. This study was linked with a cost-effectiveness
study; we aimed to sample 2,600 medical records to meet the needs of both
studies.

Sampling

During study planning in November 2007, MOH-reported data from the end of
December 2006 were used to define the clinic sample frame. By December 2006,
43,295 adults had initiated ART at 152 clinics, all of which were managed by the
MOH with funding support from several donor agencies including the U.S.
President's Emergency Plan for AIDS Relief (PEPFAR). Clinics that had
initiated <50 adults on ART by this time were excluded from the sample frame,
resulting in 58 clinics, ranging in size from 1–49 adult ART enrollees and
supporting only 1,061 adult ART patients, being excluded. Ninety-four clinics,
which had each enrolled between 50 and 3,530 adult ART patients, were included
in the sample frame; of these clinics, 12 with >1,000 enrollees were selected
with certainty, while 18 with 50–1,000 enrollees were selected using
probability-proportional-to-size sampling. All 11 provinces in Mozambique were
represented by the sample with at least one ART clinic selected from each
province. From the 30 selected clinics, ranging in site size from 70–3,530
adult ART enrollees, we aimed to randomly sample 2,600 medical records.

Multiple imputation with chained equations was used to impute missing baseline
demographic and clinical data [24]. The ice [25]–[27] procedure
in Stata was used to create 20 imputed datasets for each of two outcomes
included in multivariable analysis: Attrition and treatment failure. The
imputation model included the event indicator, all study variables, and the
Nelson-Aalen estimate of cumulative hazard [28]. Missing data were assumed
missing at random (MAR) and all patients had complete
time-to-event data. When comparing baseline characteristics among groups, the
χ2 and t-test were used to
compare categorical and continuous variables, respectively. Kaplan-Meier curves
were used to examine retention proportions stratified by baseline variables. Cox
proportional hazards regression models were used to estimate unadjusted and
adjusted hazard ratios (AHRs), 95% CIs, and p-values.
The proportional hazards assumption was assessed separately for each imputed
dataset using visual methods and the Grambsch and Therneu test [29].
Estimates were combined across the imputed datasets according to Rubin's
rules [24].
This was accomplished using SUDAAN and the mim procedure in Stata [30].

As a secondary analysis, mean CD4 count and weight change over time was estimated
to allow comparison with published literature. SAS PROC MIXED was used to fit
unweighted polynomial growth curve models with maximum likelihood (ML)
estimation to the data [31]. Random effects were specified on the intercept and
slope terms. Predicted means and 95% CIs from the polynomial growth curve
models were plotted to graphically illustrate change over time.

Results

Characteristics at ART Initiation

Data from medical records of 2,596 eligible, adult ART patients were abstracted
and analyzed. Table 1
illustrates analysis results for both original and imputed datasets; in the
following text, weighted imputed data are reported unless otherwise stated.

At ART initiation, median age of patients was 34 years, and 62% were
female of whom 16% (95% CI, 6–25%) were pregnant.
About 53% (95% CI, 50–57%) of patients were married
or in a civil union. Partner sero-status was documented in 13%
(95% CI, 11–15%) of all records. In un-weighted analysis, 37
(11%) of 330 tested partners were sero-negative.

Active tuberculosis (TB) was frequent at ART initiation with 11% of
patients receiving TB treatment. Many patients were underweight; 18%
weighed <45 kilograms (kg) at ART start. Advanced disease was common with
15% of patients diagnosed as having WHO stage IV disease.

Mortality and Attrition

Of 2,596 patients sampled, 164 died, 564 were LTFU, and 10 stopped ART
indefinitely during 4,001 patient-years of follow-up. Median follow-up duration
was 1.3 years (interquartile range, 0.7–2.2 years). Of patients who died,
56% (95% CI, 49–63%) died within 90 days of starting
ART. Of patients who were LTFU, 41% (95% CI, 35–48%)
were lost within 90 days of starting ART.

Adherence

About 71% (95% CI, 66–77%) of patients were
≥95% adherent to ART medicine pick-up appointments during the first
six months of therapy. Proportions of female and male ART patients who were
≥95% adherent to ART were not significantly different (72% vs.
70%, p = 0.12).

Discussion

This study adds to the limited number of nationally representative ART outcome
assessments from sub-Saharan Africa [6], [12], [13], and has several important
findings.

First, rates of mortality, attrition, and immunologic treatment failure for the study
period are comparable with reports from other ART programs in resource-rich [9] and
-constrained settings [6], [9], [11], [13], [17], [18], which is encouraging for program funders and managers.
Second, regimen-switch rates were very low, a finding which deserves further
research as it possibly indicates delay in switching patients from failing
first-line regimens and risk of poor longer term outcomes [20]. Third, as has been reported
from other ART programs, male sex, advanced HIV disease, and malnutrition predicted
poor outcomes, suggesting that male-specific interventions, starting ART at earlier
disease stages, and evidence-based interventions for malnourished patients, could
improve future program outcomes. Fourth, CTX prescription at ART initiation, which
was documented for about one third of patients, was associated with lower attrition
risk, highlighting the need for CTX scale-up among ART patients [32]–[35]. Fifth,
attrition rates appeared to increase as the ART program expanded, a concerning trend
that requires further research to better understand underlying causes. Finally,
documenting partner sero-status was uncommon, possibly indicating missed prevention
opportunities among sero-discordant couples [36].

Treatment Outcomes

Meta-analyses of attrition in adult ART programs in sub-Saharan Africa have
reported mean one-year attrition proportions of 25% and 20% for
the review periods of 2000-2007 [11] and 2007–2009 [18], respectively. In these
studies, LTFU accounted for between 56% [11] and 59% [18] of attrition.
Similarly, in our study, one-year attrition was 21% with LTFU accounting
for most (71%) of patient loss from the program. This relatively high
contribution of LTFU to attrition likely reflects the lack of active patient
tracing systems in most Mozambican ART facilities [9], [37] due to their cost [37].

Since recent reports show that patient death may account for 29–59%
of patients who are LTFU [38]–[42], we should consider our reported mortality and
attrition rates as best- and worst-case estimates of true mortality. Our
best-case estimate of mortality (3.4 deaths per 100 person-years) is similar to
reports from adult ART programs with passive follow-up systems (2.7 deaths per
100 patient-years [9]) but predictably lower than that reported for programs
with active follow-up systems (5.5 deaths per 100 patient-years [9]). Our
worst case estimate for true mortality (19.8 deaths per 100 person-years) is
comparable with the rate of 16.1 deaths per 100 patient-years reported for a
large Zambian cohort [6].

Similar to other programs [4]–[6], [8]–[10], [13], [17], [43]–[50], large proportions of
documented mortality (56%) and LTFU (41%) occurred within 90 days
of starting ART, highlighting the importance of this time period. Evidence based
interventions which reduce early mortality are urgently needed [51]. To limit
early LTFU from the program, the MOH is considering a pilot program to rapidly
trace all patients LTFU in the 90 days following ART initiation.

Rates of Regimen-Switch

Compared with the average regimen-switch rate for resource-constrained programs
(2.4 switches per 100 person-years, 95% CI, 2.2–2.6 [20]), our
switch rate (0.6 regimen changes per 100 person-years) was low. Limited access
to routine viral load testing has likely contributed to low regimen-switch rates
[20].
However, even compared with regimen-switch rates among programs lacking routine
viral load testing (2.0 per 100 person-years, 95% CI 1.8–2.3 [20]), our
switch rates are low. Limited access to second-line therapy, or training in its
use, may have contributed to low switch rates, especially at more peripheral
health facilities where ART is commonly managed by non-physician clinicians
[20],
[53].
Because low regimen-switch rates may indicate delay in switching patients from
failing first-line regimens, which could lead to poor long-term outcomes [20], [54] further
research to better understand the reasons for low regimen-switch rates is
planned.

Advanced HIV Disease

Similar to other reports, many patients initiated ART with WHO stage IV disease,
which was a strong predictor of attrition [5], [6], [9], [44], [47], [49], [55]–[57]. This suggests that earlier
diagnosis and ART is needed to improve program outcomes [51]. Mass HIV testing campaigns,
earlier entry into HIV care, and ensuring pre-ART care retention, will likely be
needed to reduce absolute numbers of late starters [51]. In addition, the MOH raised
the CD4 count threshold for ART initiation among adults with WHO stage I/II
disease from 200 to 250/µL in 2008, and from 250 to 350/µL in 2010
[58], which
should reduce the proportion of patients initiating ART with end-stage
disease.

Male Sex

Similar to other reports [5], [6], [8], [10], [55], male sex was associated with poorer outcomes. In our
study, males tended to initiate ART at lower CD4 counts than females, suggesting
late presentation contributed to poorer outcomes. However, even in multivariate
analysis, male sex was associated with poorer outcomes. Reasons for this are
unknown, but could relate to differences in health-seeking or adherence behavior
[59].

Malnutrition

As in other studies, our marker for malnutrition at ART initiation (weight <45
kg [60]) was
independently associated with poor outcomes. In Mozambique, the relative
importance of underlying causes of malnutrition among HIV-infected persons is
not well understood and deserves further research [61]. Food supplementation and
empiric TB treatment for malnourished patients are interventions which require
evaluation [62].

Failure to Prescribe CTX

Although CTX prescription is recommended for all ART patients in Mozambique
throughout therapy, few (31%) received this drug at ART initiation during
2004–2007. Reasons for this are unknown but may include CTX supply
shortfalls and clinician concerns about CTX drug resistance development [32], [33], [63].

Although several studies have demonstrated an additional benefit of CTX for ART
patients [32]–[35], reasons for this are not
fully understood [32]. In Mozambique, where malaria is an important cause
of mortality among ART patients [64], the prophylactic action
of CTX against this disease [32], may partly explain its association with improved
treatment outcomes.

Additional in-service training for ART-service providers is planned to rapidly
scale-up CTX prescription. Further, CTX procurement and distribution procedures
are being reviewed to ensure that all ART delivery sites have adequate CTX
supplies.

Temporal Trends in Attrition

As the ART program expanded during 2004 through 2007, attrition risk for newly
enrolled adult ART patients increased, a temporal trend which has been observed
in other programs in resource-constrained settings [65], [66]. Yearly increases in
observed LTFU due to undocumented transfer of patients to more peripheral
facilities during the decentralization process, may explain the increases in
observed attrition rates [67], [68]; however, further research to establish the reasons
for increasing rates of attrition is urgently needed [65].

Partner HIV Counseling and Testing

The low proportion of records with documented partner sero-status is concerning
because partner HIV counseling and testing (HIV-CT) can facilitate entry into
HIV care for infected individuals or appropriate prevention strategies for
uninfected partners [36], [69]–[76]. Poor completion of the
partner sero-status field in standard MOH medical records may be due to several
barriers including hesitancy of patients to disclose HIV status, partner refusal
to be tested, or loss to follow-up of the patient before the field can be
filled. Further research to identify and overcome these barriers is needed.

Limitations

Limitations primarily relate to the fact that these analyses were based on
routinely collected data, which were incomplete for certain baseline and
follow-up clinical characteristics.

Summary

Treatment outcomes were comparable with reports from other ART programs; however,
the low ART regimen-switch rates and the increasing attrition rates during
program expansion are concerning findings which deserve further research.
Immediate public health responses that may improve treatment outcomes include
initiation of ART at earlier disease stages, especially among males, scale-up of
CTX, and evidence-based interventions for malnourished patients; in addition,
scale-up of partner HIV-CT could significantly contribute to national HIV
prevention efforts.

Acknowledgments

The authors would like to acknowledge the health care providers in Mozambique's
antiretroviral therapy clinics without whom this study would not have been
possible.

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